A5009077731- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- Genomics and Chromatin Dynamics
- Renal and related cancers
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Animal Genetics and Reproduction
- DNA and Nucleic Acid Chemistry
- DNA Repair Mechanisms
- Prostate Cancer Treatment and Research
- Circular RNAs in diseases
- Biochemical and Molecular Research
- Sarcoma Diagnosis and Treatment
- Wnt/β-catenin signaling in development and cancer
- FOXO transcription factor regulation
- Tissue Engineering and Regenerative Medicine
- Caveolin-1 and cellular processes
- Genetics and Neurodevelopmental Disorders
- Adenosine and Purinergic Signaling
- Enzyme Structure and Function
- Gene Regulatory Network Analysis
- RNA Interference and Gene Delivery
- Erythrocyte Function and Pathophysiology
- 3D Printing in Biomedical Research
- Cell Adhesion Molecules Research
Max Planck Institute for Molecular Biomedicine
2015-2023
Georgetown University
2006-2013
Georgetown University Medical Center
2007-2013
Zero to Three
2009
Oct4 is widely considered the most important among four Yamanaka reprogramming factors. Here, we show that combination of Sox2, Klf4, and cMyc (SKM) suffices for mouse somatic cells to induced pluripotent stem (iPSCs). Simultaneous induction Sox2 in fibroblasts triggers immediate retroviral silencing, which explains discrepancy with previous studies attempted but failed generate iPSCs without using vectors. SKM could partially activate pluripotency network, even Oct4-knockout fibroblasts....
Abstract The transcription factors OCT4 and SOX2 are required for generating induced pluripotent stem cells (iPSCs) maintaining embryonic (ESCs). associate bind to DNA in different configurations depending on the arrangement of their individual binding elements. Here we have investigated role OCT4-SOX2-DNA assemblies regulating inducing pluripotency. To this end, generated mutants that interfere with specific OCT4-SOX2 heterodimer assessed ability generate iPSCs rescue ESC self-renewal. Our...
Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission demonstrated mice rats. By swapping structural elements between Sox2 Sox17, we built chimeric super-SOX factor, Sox2-17, that enhanced in five tested species: mouse, human, cynomolgus monkey, cow, pig. A swap alanine to valine at the interface Oct4 delivered gain function by...
Transcription factor (TF) proteins bind to DNA regulate gene expression. Normally, accessibility is required for their function. However, in the nucleus, often inaccessible, wrapped around histone nucleosomes forming chromatin. Pioneer TFs are thought induce chromatin opening by recognizing binding sites on nucleosomes. For example, Oct4, a master regulator and inducer of stem cell pluripotency, binds sequence-specific manner. Here, we reveal structural dynamics that mediate Oct4 from...
The transcription factor Oct4 is essential for the maintenance and induction of stem cell pluripotency, but its functional roles are not fully understood. Here, we investigate functions by depleting subsequently recovering it in mouse embryonic cells (ESCs) conducting a time-resolved multiomics analysis. depletion leads to an immediate loss binding enhancers, accompanied decrease mRNA synthesis from target genes that part transcriptional network maintains pluripotency. Gradual enhancers does...
Abstract Pioneer transcription factors are proteins that induce cellular identity transitions by binding to inaccessible regions of DNA in nuclear chromatin. They contribute chromatin opening and recruit other regulatory elements. The structural features dynamics modulating their interaction with nucleosomes still unresolved. From a combination experiments molecular simulations, we reveal here how the pioneer factor master regulator pluripotency, Oct4, interprets enhances nucleosome...
Oct4 collaborates primarily with other transcriptional factors or coregulators to maintain pluripotency. However, how exerts its function is still unclear. Here, we show that the linker interface mediates competing yet balanced protein interactions are crucial for maintaining mutant embryonic stem cells (ESCs) decreased expression of self-renewal genes and increased differentiation genes, resulting in impaired ESC early development. The mutation interrupts interactome. In ESCs, interaction...
Article22 December 2016Open Access Source Data Changing POU dimerization preferences converts Oct6 into a pluripotency inducer Stepan Jerabek orcid.org/0000-0002-3902-1939 Max Planck Institute for Molecular Biomedicine, Münster, Germany Search more papers by this author Calista KL Ng of Medical Biology, Singapore City, Guangming Wu Marcos J Arauzo-Bravo Biodonostia Health Research Institute, San Sebastián, Spain IKERBASQUE, Basque Foundation Science, Bilbao, Kee-Pyo Kim Daniel Esch Vikas...
OCT4 (also known as POU5F1) plays an essential role in reprogramming. It is the only member of POU (Pit-Oct-Unc) family transcription factors that can induce pluripotency despite sharing high structural similarities to all other members. Here, we discover OCT6 POU3F1) elicit reprogramming specifically human cells. OCT6-based does not alter mesenchymal-epithelial transition but attenuated through delayed activation network comparison with OCT4-based Creating a series reciprocal domain-swapped...
Caveolin-1 (CAV1) has been implicated in the regulation of several signaling pathways and oncogenesis. Previously, we identified CAV1 as a key determinant oncogenic phenotype tumorigenic activity cells from tumors Ewing's Sarcoma Family (ESFT). However, possible involvement chemotherapy resistance commonly presented by an ESFT subset not established to date. This report shows that expression determines sensitivity clinically relevant chemotherapeutic agents. Analyses endogenous levels...
Highlights•Individually expressed BKSM generate iNSCs without a transient pluripotent state•Polycistronic expression produces Brn4-Klf4 fusion protein•The protein gains the ability to induce pluripotency•A shift in Brn4 binding from OctOct SoxOct motif enables induction of pluripotencySummarySimultaneous Oct4, Klf4, Sox2, and cMyc induces pluripotency somatic cells (iPSCs). Replacing Oct4 with neuro-specific factor leads transdifferentiation fibroblasts into induced neural stem (iNSCs)....
It is generally accepted that the functional activity of biological macromolecules requires tightly packed three-dimensional structures. Recent theoretical and experimental evidence indicates, however, importance molecular flexibility for proper functioning some proteins. We examined high resolution structures proteins in various categories with respect to secondary structure assessment. The latter was considered as a characteristic inherent polypeptide chain. found functionally competent...
Abstract Previous reports showed that PCPH is mutated or deregulated in some human tumors, suggesting its participation malignant progression. Immunohistochemical analyses not expressed normal prostate, but expression increases along cancer progression stages, being detectable benign prostatic hyperplasia, highly intraepithelial neoplasia, and remaining at high levels prostate carcinoma. Experiments designed to investigate the contribution of phenotype cells overexpression PC-3 cells, which...
An engineered SOX17 variant with point mutations within its DNA binding domain termed SOX17FNV is a more potent pluripotency inducer than SOX2, yet the underlying mechanism remains unclear. Although wild-type was incapable of inducing pluripotency, outperformed SOX2 in mouse and human reprogramming. In embryonic stem cells, could replace to maintain despite considerable sequence differences upregulated genes expressed cleavage-stage embryos. Mechanistically, co-bound OCT4 cooperatively...
Expression of the ENTPD5/mt-PCPH oncoprotein and overexpression normal ENTPD5/PCPH protein contribute to malignant transformation diverse mammalian cell types, PCPH is mutated and/or deregulated in various human tumor types. or mt-PCPH caused similar phenotypes, yet effects promoted by expression were consistently substantially greater. ATP depletion increased stress‑resistance are phenotypes commonly associated with expression. It was suggested that intrinsic nucleoside triphosphate...
Abstract Transcription factor (TF) proteins bind to DNA regulate gene expression. Normally, accessibility is required for their function. However, in the nucleus often inaccessible, wrapped around histone nucleosomes forming chromatin. Pioneer TFs are thought induce chromatin opening by recognizing binding sites on nucleosomes. For example, Oct4, a master regulator and inducer of stem cell pluripotency, binds sequence specific manner. Here we reveal structural dynamics that mediate Oct4...
ABSTRACT The discovery of induced pluripotent stem cell (iPSC) technology by Shinya Yamanaka has truly enabled the field. After 16 years intense research, delivery methods and culture media have improved but original factors—Oct4, Sox2, Klf4, Myc (OSKM)—remain central for driving reprogramming. Here we define structural elements in chimeric Sox2/Sox17 transcription factors that rescued ability nonfunctional Oct to induce pluripotency. Most importantly, discovered a single amino acid swap...
Abstract Pioneer transcription factors are proteins that induce cellular identity transitions by binding to inaccessible regions of DNA in nuclear chromatin. They contribute chromatin opening and recruit other regulatory elements. The structural features dynamics modulating their interaction with nucleosomes still unresolved. From a combination experiments molecular simulations, we reveal here how the pioneer factor master regulator pluripotency, Oct4, interprets enhances nucleosome...
Abstract Ewing's sarcomas (EWS) are tumors typically formed by undifferentiated small round cells that predominantly affect children and young adults. The aggressiveness of EWS is illustrated both the fact about 25-30% patients present with metastases at diagnosis elevated rate lethal recurrence among them. In spite therapeutic combinations including chemotherapy, radiation surgery, 5-year disease-free survival for has remained low many years. Poor prognosis, long-term side effects point to...